Fluid delivery systems, devices and methods for delivery of hazardous fluids

ABSTRACT

A system for injecting a patient, includes a container enclosing a hazardous pharmaceutical; a first pump to deliver a hazardous pharmaceutical to a patient and a fluid path operably connected to the first pump, the container, and the patient. The system further includes a hazardous material containment suitable to confine the hazardous pharmaceutical during connection of the hazardous pharmaceutical container to the fluid path.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.10/821,210, filed Apr. 8, 2004, now patented, and claims the benefit ofU.S. Provisional Patent Application Ser. No. 60/461,152, filed Apr. 8,2003, the disclosures of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates generally to fluid delivery systems, tofluid delivery devices and to methods of fluid delivery, and,especially, to fluid delivery systems of hazardous medical fluids,devices for use therein and to methods of delivering hazardous medicalfluids to a patient. Current angiographic practice uses X-ray imaging tovisualize the inside of the body. Physicians deftly maneuver cathetersto a desired blood vessel. X-ray absorbing contrast is injected so thatthe vessel and downstream vessels can be clearly seen on the X-raydisplay or film. Using the resultant image, a physician makes adiagnosis and determines appropriate treatment. In interventionalprocedures, treatment is performed using injection catheters,atherectomy devices, stents, or any one of many interventional devices.Often the interventional treatment is performed during the angiographicprocedure, although sometimes treatment is performed at a later time.

During normal angiographic procedures, in addition to contrast it iscommon to inject saline to flush contrast from the catheter, to keep thecatheter lumen open (unclotted), and/or to act as a fluid path formeasuring blood pressure. Often the doctor performs the injections byhand, particularly for coronary injections. In some cases, saline isgravity fed.

For peripheral injections, and sometimes for coronary injections,powered injectors are used to inject the contrast because of its highviscosity and the high pressures required to drive contrast throughsmall catheter diameters. Powered injectors can, for example, developpressures up to 1200 psi in such injections. The pressure range used insuch injections is well above the pressure a person can practicallydevelop via hand injection. U.S. Pat. Nos. 5,494,036, 6,339,718,5,843,037, 5,840,026, 5,806,519, 5,739,508, and 5,569,181, assigned tothe assignee of the present invention, which are incorporated herein byreference, disclose the use of powered injector systems that are capableof injecting contrast, saline, and other fluids, either at the same timeor in sequence.

In thrombolytic therapy, a doctor places a catheter to study a blockageof a vessel. The doctor then uses a plain catheter or one of manyspecial thrombolytic catheters to inject a thrombolytic agent into theclot. Sometimes the injection is performed using periodically pulsedhigh-pressure injections to drive the thrombolytic agent into the clotand speed its breakdown. Examples of injectors suitable for use inthrombolytic procedures include the Pulse*Spray Injector Model PSI-1available from AngioDynamics of Queensbury, N.Y. and the PulseThrombolytic Pump PTP1 available from Linet Compact s.r.o. of the CzechRepublic.

A difficulty with such currently available injection devices is therequirement that the doctor manipulate the fluid path, sometimes havingto disconnect the manual contrast injection syringe and connect thethrombolytic injector. This manipulation takes time, and carries somerisk of operator error, including inadvertent biological contamination.

Another interventional procedure under development involves theinjection of gene therapies. The goal of one type of gene therapy is tocause the heart muscle to express a gene that causes growth of new bloodvessels to nourish heart muscle in which supply arteries have becomesignificantly narrowed by disease. In one type of such gene therapy, thegene therapy DNA is contained in a non-replicating virus. When injectedinto the body, this virus transfects cells with the contained DNA. Asthe virus does not contain the DNA required for replicating the virus,it does not multiply and cause disease. These viruses can transfect anycells that they contact with the gene therapy DNA. For this reason, itis important to ensure that the vector viruses are delivered to targettissues only, and to make sure that the hospital personnel aresufficiently protected from contact with the vector virus.

Another application of gene therapy is to block angiogenesis as a way toreduce tumor growth. In this application it is also important that thegene therapy be delivered to the target tissue and that delivery tohealthy tissue and health care workers be minimized There are also manyother gene therapy applications under study, for example treating cysticfibrosis and muscular dystrophy.

In a representative procedure using an adenovirus gene therapy product,practitioners perform the following steps: (1) storing frozen vials inthe pharmacy; (2) in a pharmacy hood, using gloves and proper technique,thawing the bottle with the gene therapy drug in the hand, avoidingagitation; (3) using a needle, pulling a few ml of drug into a handsyringe, for example a 10 ml syringe; (4) adding a few ml of saline todilute the drug; (5) placing the hand syringe in a syringe holder fortransport to the interventional suite to preserve the sterility of theoutside of the syringe (the thawed drug has to be used within severalhours); (6) for use in the interventional suite, donning goggles andmasks (doctors, nurses, technicians) with M-95 filters to protectagainst infection from airborne viruses; (7) purging the fluid lines ofair; (8) diluting the drug further if needed; (9) positioning thecatheter in the desired vessel using normal angiographic equipment(manifolds, catheters, guidewires) and technique (normally this is adeep subselective placement to avoid any reflux of contrast or drug intothe aorta, where it would be distributed systemically); (10) verifyingthe placement of the catheter with a contrast injection; (11) optionallyflushing the manifold and/or catheter with saline by removing thecontrast syringe and attaching the saline syringe; (12) disconnectingthe saline syringe; (13) connecting the gene therapy syringe; (14)injecting by hand approximately 1 to 5 milliliters of the gene therapydrug over 1 to 2 minutes; (15) disconnecting the gene therapy syringe;(16) connecting the saline syringe; (17) injecting a few ml of salineover the same time period (e.g., 1 to 2 minutes) to flush the genetherapy drug out of the fluid path and into the patient; (18)disconnecting the saline syringe; (19) reconnecting the contrastsyringe; (20) injecting contrast to confirm that the catheter has notmoved; (21) repositioning the catheter for the next injection; (22)repeating prior steps until all vessels are injected; and (23) disposingof the disposable parts of the systems (as biohazardous material).

There are a number of drawbacks or unmet needs with the current systemsand processes for gene therapy delivery. For example, an enclosedpreparation hood is required.

Furthermore, disconnecting and reconnecting multiple syringes fordelivering contrast, saline, and drugs is time consuming and increasesthe risk that some of the drug may be spilled or aerosolized and thusinfect the operator and/or the patient in an undesired fashion, or thatthe drug may be contaminated.

Moreover, it is very difficult for a human to inject a fluid at a steadyrate, especially for slow rates (ml/min) extending more than a minute.Motion at a slow rate suffers from stick-slip friction in the syringe,and it takes significant concentration to do it for two 1-2 minuteperiods up to five times in a procedure. There is significant risk ofaccidental jerking or bolus injection that either wastes drug or causesit to reflux into the aorta and travel elsewhere in the body. Also, assyringes are connected and disconnected, the plunger can beunintentionally bumped and a bolus of drug injected into the patient orexpelled into the environment. Additionally, the changeover time fromdrug syringe to saline syringe causes an uncontrolled break in therapyinjection. As the drug is susceptible to clump formation if agitated,manually connecting and disconnecting the syringe provides opportunitiesfor agitation and clumping.

As mentioned, deep sub-selective catheter placement is needed to avoiddrug reflux into the aorta. However, such catheter placement introducesthe risk of reducing blood flow through that artery and increases thepossibly of causing dissections. Moreover, deep sub-selective catheterplacement is more difficult technically to achieve.

Multiple manual manipulations of syringes and the manifold connected tothe catheter in the patient increases the risk that the catheterposition will be accidentally shifted from optimum placement.

Multiple manual manipulations also increases the risk of errors, such asinjecting saline first, and then the drug, and thus having the drug inthe catheter being injected into the aorta when it is being moved fromone vessel to another.

All procedures that provide access to a patient's blood vessels requirethat a sterile field be created and maintained to protect the patientagainst infections. Operators with sterile gloves cannot touch anythingthat is not sterile, and operators with non-sterile gloves cannot touchanything that goes into the sterile field. In addition, anything thattouches the patient, and especially anything that touches bodily fluids,such as blood, has to be disposed of as a biohazardous material. And, asmentioned above, the gene therapy drug itself, even when uncontaminated,poses a biohazard.

Similarly, aerosolization or spillage of chemotherapy agents duringpreparation or delivery can create hazardous conditions for health careworkers or nearby people. Preparation of chemotherapy agents isgenerally done in a pharmacy in a hood, to protect the pharmacy workers.Chemotherapy agents can be administered intra-arterially into thevessels supplying nourishment to tumors. This has the benefit of givingthe tumor a very high dose while keeping the total systemic dose (andthus tissue damage and side effects) to a minimum. It has the downsideof requiring the occupation of the expensive facilities of acatheterization or special procedures suite. More commonly, chemotherapydrugs are administered through peripheral intravenous catheters, PICClines, central venous catheters, or infusion ports. The drug in injectedwith a hand syringe or an infusion pump, often into a side port of aninfusion line connected to one of the venous access devices mentionedabove. It is commonly done in the patient's room, an outpatient clinic,or more recently in the patient's home. The making and breaking ofconnections provides the opportunity for drug spillage or aerosolizationand thus transmission to nearby personnel. In chemotherapyadministration masks and goggles are not routinely used.

With intra-arterial administration of chemotherapy, the tumor receivesthe drug directly. With intra-venous administration, many chemotherapyagents damage the veins in which they are injected. This causes localreactions and pain, and it makes it difficult for health care workers tosubsequently be able to insert a catheter into the vein.

A third situation which can involve the delivery to a patient ofpotentially hazardous drugs with associated concern about exposure ofother personnel are intramuscular and subcutaneous injections. There aremany clinical trails and much research being focused on intramuscularinjection of gene therapies and biologics. The needle of a hand syringeis inserted through the skin into the target muscle. Then a controlledamount of drug is injected. Each time the needle is removed from onesite and moved to another there is the opportunity for aerosolizationand/or spillage since the drug is present at the needle tip.

While it is not yet widely done for gene therapies, inhalation of drugsis a common practice for asthma drugs, is being studied for other drugs,and is another application in which nearby personnel can inadvertentlybe contaminated by the drug being administered to a patient. As morepotent drugs are administered this way, the effects of accidentalexposure will become more prevalent. In this case, the drug isintentionally delivered as an aerosol of a liquid or a power, so theproblem is particularly severe. All of the aerosol that is put into theair conduits and the patient's airways is not deposited in the patient'sbody. Thus there is a significant amount of aerosol that could beaccidentally released.

It is desirable to develop systems, devices and methods of delivering oradministering hazardous pharmaceuticals to patient that reduce and/oreliminate one or more of the problems with current systems, devices andmethods described above as well as other problems.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a system for injecting apatient including a container enclosing a hazardous pharmaceutical; afirst pump to deliver a hazardous pharmaceutical to the patient and afluid path operably connected to the first pump, the container, and thepatient. The system further includes a hazardous material containmentsuitable to confine the hazardous pharmaceutical during connection ofthe hazardous pharmaceutical container to the fluid path.

The hazardous materials containment can, for example, include a sealableopening adapted to enable placement of the container in the hazardousmaterials containment prior to connecting the container to the fluidpath. The hazardous materials containment can also include a connectorin fluid connection with a conduit passing through the hazardousmaterials containment in a sealed manner. In that embodiment, theconnector is adapted to make a fluid connection with the container. Theconduit is adapted to be connected to the fluid path.

The system can include at least second pump operably connected to thefluid path to deliver at least one nonhazardous fluid to the patient.The nonhazardous fluid can, for example, be a fluid suitable to flushthe medication out of the fluid path and into the body or a fluidsuitable to dilute the hazardous pharmaceutical. The nonhazardous fluidcan, for example, be saline. The system can further include a third pumpoperably connected to the fluid path, which is in fluid connection witha source of a third fluid (for example, a contrast fluid).

The system can also include a waste container in fluid connection withthe fluid path. Preferably, the waste container is suitable to contain ahazardous pharmaceutical.

The system can further include at least one valve to control flowthrough the fluid path. The system can also include a controller tocontrol the operation of at least the first pump and the second pump. Auser interface can be in operative connection with the controller.

In one embodiment, the hazardous material containment includes atemperature regulator to control the temperature of the hazardousmaterial container.

The hazardous material containment can include a flexible barrier tosurround the hazardous pharmaceutical container. The hazardous materialcontainment can also include a container having a removable lid toenable placement of the hazardous pharmaceutical container within thehazardous material containment. In this embodiment, the hazardousmaterial containment further includes a sealing bather through which afluid path element can pass to be placed in fluid connection with thehazardous pharmaceutical container. The sealing barrier is suitable toprevent passage of the hazardous pharmaceutical to the environmentoutside of the hazardous material containment. The hazardous materialcontainment can also include at least one sealing member which forms aseal with the hazardous pharmaceutical container.

The first pump and other pump(s) of the system can be included in asingle injector. In one embodiment, each of the pumps is energized. Theterm “energized” or “apparatus energized” refers to the application ofenergy (for example, mechanical energy or thermal energy), other than bydirect manual manipulation. Typically, electrical energy or storedmechanical energy is used in energizing the devices of the presentinvention.

The system can further include a measurement apparatus that detects aphysiological signal of the patient and a controller that controls fluiddelivery from at least one of the first pump and the second pump basedupon the physiological signal to control (for example, synchronize)fluid delivery in relation to an organ function.

In one embodiment of the system of the present invention, the containeris a vessel in which the hazardous pharmaceutical is distributed by amanufacturer. The container can enclose sufficient hazardouspharmaceutical for delivery to multiple patients. In another embodiment,the container is filled with the hazardous pharmaceutical using aloading device that maintains biohazardous materials containment. Onceagain, the filled container can enclose sufficient hazardouspharmaceutical for delivery to multiple patients.

The fluid path of the system can include a catheter which is adapted toterminate in a blood vessel of the patient. In one embodiment, thecatheter includes two lumens arranged such that flow from the outerlumen substantially surrounds flow from the inner lumen. A catheter canbe connected to the fluid path of the system by a connector thatprovides biohazard containment during connection.

In one embodiment of the system of the present invention the fluid pathcomprises at least two fluid path elements that are connected by atleast one connector that provides biohazard containment duringconnection.

In an embodiment of the system of the present invention including acontroller, the controller can change flow rate over time. For example,the controller can changes the flow such that there are periods of timeduring which flow rate is increased.

In another aspect, the present invention provides an assembly forconnection to an injector. The injector includes a retention mechanismto retain the assembly and a pressurizing mechanism to pressurize one ormore fluids within the assembly for delivery to a patient. The assemblyincludes at least a first compartment defining an enclosure adapted toenclose a hazardous pharmaceutical container enclosing a hazardouspharmaceutical. The first compartment is adapted to prevent hazardousmaterials from escaping from the first compartment into the surroundingenvironment. The first compartment includes a first connector toestablish a fluid connection with the hazardous pharmaceutical vesseland at least a first outlet in fluid connection with the firstconnector. The assembly can further include at least a secondcompartment adapted to contain a fluid other than the hazardouspharmaceutical, the second compartment being in fluid connection withthe first outlet.

In another aspect, the present invention provides a system for injectinga pharmaceutical into a local circulation associated with an organ of apatient. The system includes a first pump for injecting the biohazardouspharmaceutical into the local circulation; a fluid path operablyconnected to the first pump and disposed between the first pump and thepatient; a second pump operably connected to the fluid path forinjecting a fluid sufficient to flush the pharmaceutical out of thefluid path and into the patient; a measurement apparatus that detects aphysiological signal of the patient; and a controller that controlsfluid delivery from at least one of the first pump and the second pumpbased upon the physiological signal to control (for example,synchronize) fluid delivery in relation to an organ function. In oneembodiment, the physiological signal is related to heart phase. Thesynchronization relative to heart phase can, for example, prevent refluxof the pharmaceutical from a local circulation into a system circulationof the patient. In another embodiment, the physiological signal isrelated to respiration phase.

In a further aspect, the present invention provides a system forinjecting a patient, including: a first pump for delivering a hazardouspharmaceutical to a patient and a fluid path operably connected to thefirst pump and disposed between the first pump and the patient. Thefirst fluid path includes at least one fluid path element. The systemfurther includes a second pump operably connected to the fluid path forinjecting a fluid sufficient to flush the hazardous pharmaceutical outof the fluid path and into the patient. The system also includes ahazardous material containment to confine hazardous materials during atleast one of establishment, modification, and disposal of fluid pathelements.

In another aspect, the present invention provides a method ofadministering a hazardous pharmaceutical to a patient, including:operably connecting a container in which the hazardous pharmaceutical isdistributed to a fluid path in operative connection with a pump. Thepump is adapted to administer the hazardous pharmaceutical to thepatient. The method can further include placing the container in ahazardous materials containment suitable to confine the hazardouspharmaceutical prior to and during connection of the container to thefluid path. The hazardous materials containment can include a sealingseptum through with connection with the container is made.

In another aspect, the present invention provides a catheter includingan outer conduit, and an inner conduit positioned within the outerconduit and having a diameter smaller than the outer conduit. The volumebetween the outer conduit and the inner conduit defines a first lumenadapted to deliver fluid to the patient. The inside diameter of theinner conduit defines a second lumen adapted to deliver a fluid to thepatient. In one embodiment, the inner conduit ends rearward of the outerconduit. The flow from the inner conduit can be substantiallycircumferentially surrounded by the flow from the outer conduct.

In a further aspect, the present invention provides a containerincluding a flexible sealing member that cooperates with a connector tocreate a biohazard seal during connection of the container to theconnector. The flexible sealing member can, for example, becircumferential. The flexible sealing member can also be axiallycompressed during connection.

In another aspect, the present invention provides a connector includinga first member and a second member. At least one of the first member orthe second member includes a biohazard seal adapted to containbiohazardous material during connection of the first member and thesecond member.

In another aspect, the present invention provides a container for abiohazardous material including a first septum sealing a port into thecontainer and a second septum sealing the port. The second septum isspaced from the first septum.

In an another aspect, the present invention provides a system fortransferring a pharmaceutical, including: a first container enclosing ahazardous pharmaceutical; a second container to receive the hazardouspharmaceutical; a first pump to deliver a hazardous pharmaceutical fromthe first container to the second container; a fluid path operablyconnected to the first pump, the first container, and the secondcontainer; and a hazardous material containment suitable to confine thehazardous pharmaceutical during connection of the first container to thefluid path.

In a further aspect, the present invention provides a syringe loadingdevice including at least a first compartment adapted to removablyreceive a first syringe. The first syringe includes a plunger slidablydisposed therein. The first compartment includes a syringe connectoradapted to make a fluid connection with the first syringe. The syringeloading device further includes a first container dock adapted to form asealed engagement with a first fluid container which contains ahazardous pharmaceutical. The first container dock includes a firstcontainer connector adapted to make a fluid connection with the firstcontainer. The first container connector is in fluid connection with thesyringe connector. The syringe loading device further includes anactuator adapted to apply force to the first syringe plunger to drawfluid from the first container into the first syringe. The syringeloading device of can further include at least a second container dockadapted to form an engagement with a second fluid container. The secondcontainer dock includes a second container connector adapted to make afluid connection with the second container. The second containerconnector is in fluid connection with the syringe connector. The syringeloading can further include a switch to control whether the fluid isdrawn into the syringe from the first container or the second container.

In still a further aspect, the present invention provides an injectorincluding a first compartment adapted to receive a first syringe. Thefirst syringe has a hazardous pharmaceutical within a barrel thereof andincludes a plunger slidable disposed within the syringe. The injectorfurther includes a first plunger drive in operative connection with thefirst compartment; an energy storage mechanism adapted to storemechanical energy applied manually to the first plunger drive and asecond compartment adapted to receive a second syringe. The secondsyringe also includes a plunger slidably disposed within the syringe.The injector further includes a second plunger drive in operativeconnection with the second compartment; an energy storage mechanismadapted to store mechanical energy applied manually to the secondplunger drive; and at least one control to regulate the application ofstored mechanical energy to the plunger of the first syringe and to theplunger of the second syringe.

The present invention provides a number of improvements over currentmethods for delivery of hazardous pharmaceutical to patients, Forexample, the present invention provides enclosures sufficient to protectthe operator and patient during preparation and loading of the drug.Certain embodiments of the present invention incorporate an integratedfluid path, preferably a closed path, for both sterility and the safetyfor operators. The present invention likewise provides energized pumpsor regulators to provide consistent, steady flow rates over time framesnot practical for humans.

The systems of the present invention can, for example, incorporatediagnostic information (flow rate to reflux) to set therapeuticparameters. An integrated multi-fluid controller/sequencer can also beincorporated in the systems of the present invention to make procedureseasier for the operator, and more consistent and safer for the patient.The present invention can also provide, a record of the fluidadministration parameters.

The systems, devices and methods of the present invention can be usedwith X-ray, MR, CT, ultrasound or other medical imaging modalities, andcan beneficially inject many fluids and types of fluids in addition togene therapy drugs.

BRIEF DESCRIPTION OF THE DRAWINGS

Other aspects of the invention and their advantages will be discernedfrom the following detailed description when read in connection with theaccompanying drawings, in which:

FIG. 1 illustrates an example of a fluid delivery system currently usedin gene therapy.

FIG. 2 illustrates one embodiment of a fluid delivery system of thepresent invention.

FIG. 3 illustrates a schematic diagram of pulsed injection to eliminatereflux.

FIG. 4 illustrates another embodiment of a biohazard container of thepresent invention for use with a biohazardous drug or pharmaceuticalbottle.

FIG. 5A, 5B, and 5C illustrates other embodiments of a biohazardcontainment for a biohazardous pharmaceutical container.

FIG. 6 illustrates a biohazard container adapted for use with a handsyringe.

FIG. 7A illustrates a perspective view of a syringe loader including anhazardous material enclosure.

FIG. 7B illustrates another perspective of the syringe loader of FIG. 7Ain which a syringe is being unloaded into the sterile field.

FIG. 7C illustrates a perspective view of one embodiment of an internalfluid path for use in the syringe loader of FIG. 7A.

FIG. 8A illustrates one embodiment of a pump and a multi-chamber fluidcontainer of the present invention in a disconnected state.

FIG. 8B illustrates a perspective view of the pump and a multi-chamberfluid container of FIG. 7A in a connected state.

FIG. 8C illustrates another perspective view of the pump and amulti-chamber fluid container of FIG. 7A in a connected state with thedrug container ready for insertion.

FIG. 9 illustrates an embodiment of pump mechanism of the presentinvention used to automate fluid delivery from multiple preparedsyringes.

FIG. 10A illustrates a perspective view of an embodiment of a poweredinjector or pump of the present invention for use with two front-loadingsyringes.

FIG. 10B illustrates the pump of FIG. 10A supported on the arm of amobile support system in association with an angiographic injector.

FIG. 10C illustrates the pump of FIG. 10A attached to a supportextending from the patient table of an imaging system.

FIG. 11A illustrates a side, cross-sectional view of the end portion ofan embodiment of a generally concentric, dual lumen catheter.

FIG. 11B illustrates an end view of the catheter of FIG. 11A.

FIG. 11C illustrates a side, cut away view of the catheter of FIG. 11Awith saline and a bolus of a hazardous pharmaceutical flowingtherethrough.

FIG. 11D illustrates the resultant flow profile through a patientvessel.

FIG. 12 illustrates an additional embodiment of the present invention.

FIGS. 13 a, 13 b, 13 c and 13 d illustrate several embodiments ofconnectors for joining two fluid path segments.

DETAILED DESCRIPTION OF THE INVENTION

A system currently used for the injection of a gene therapy drug isillustrated in FIG. 1. In FIG. 1, a patient 1 has a catheter 31 insertedvia a femoral (leg) artery into the arteries nourishing the patient'sheart 2. A number of catheters with single or dual side-by-side lumensare commonly used. The catheters can have just an end hole, or multipleside holes to increase the mixing of the drug with the blood. Aninfusion catheter slid inside a guiding catheter is also commonly used.Other arteries can be used for accesses as well. The external end of acatheter 31 is connected via a connector to a manifold 30, eitherdirectly or with an intermediate piece of tubing (not shown). Othercommon angiographic equipment and personnel such as a guide wire, ahemostasis valve, an X-ray imaging system, an MR imaging system, anultrasound imaging system, or other imaging equipment, as well asphysicians and nurses are not shown in FIG. 1.

Manifold 30 has several valves, typically three or four, which in thesystem of FIG. 1 connect to three lines. Line 22 is connected to a bloodpressure measuring device (not shown), line 21 is connected to a salinebag, bottle, container, or reservoir (not shown), and line 20 isconnected to a contrast bag, bottle, container, or reservoir (notshown). A hand-operated syringe 10 is used to inject contrast or saline,depending upon whether it is filled from line 20 or from line 21. Theregion surrounding the vascular access site and nearby areas of thepatient are covered by sterile cloths and the exposed skin near thevascular entry point is sterilized. There is typically an adjacent worksurface or cart that has a flat sterile surface 19 to hold sterileinstruments and supplies ready for use. For the situation in which agene therapy drug is to be injected, syringe 12 contains the genetherapy drug and syringe 11 contains the saline used to follow the genetherapy injection and flush the gene therapy drug from the fluid pathand into the patient. As described above, the doctor manually connects,fills, injects, and disconnects syringes 10, 11, and 12 to achieve thedesired sequence of fluid delivery. And each time a connection is made,the doctor has to ensure that bubbles are not created that can beinjected into the patient and cause strokes or damage to other organs.

FIG. 2 illustrates one embodiment of a fluid delivery system of thepresent invention. In the embodiment of FIG. 2, patient 1 has a catheter31 inserted via a femoral approach into the patient's heart 2. Catheter31 is connected to a manifold 30 to enable injection of various fluids.Syringe 10 can be filled with contrast from line 20 and then injected.In this embodiment, syringe 10 is operated by a mechanical injector 40including a piston 40 a that pushes or pulls on the syringe plungerextension, thereby moving fluid in and out of syringe 10. An injector orsyringe pump, such as the ProVis® angiographic injector available fromMedrad, Inc. of Indianola, Pa., can, for example, be used as pump 40.

Pump 42 delivers the gene therapy drug or other drug. In thisembodiment, the drug remains in its container 52 and is pumped from thecontainer by a peristaltic pump 42. The drug flows though tubing 24 cand then tubing 24 a into the manifold and thence into patient 1. Tubing24 c and 24 a can, for example, be microbore tubing to minimize theamount of fluid or dead space in the tubing itself. In the embodiment ofFIG. 2, pump 42 and the drug containing apparatus are outside thesterile field. The fluid is brought into the sterile field throughsterile tubing 24 a. Drug container 52 can be any container whichpreserves the sterility and utility of the drug including, for exampleglass bottles, bags, carpules, or prefilled syringes. If container 52(or any other fluid container in the system) is rigid, a vacuum will becreated as fluid is pulled out. There are several methods to eliminatethis problem. For example, air can be injected into the container beforeremoval of the fluid, or the needle or spike used to remove the fluidcan be vented with a hydrophobic filter or with a one way valve andfilter that allows sterile air to enter the container as the fluid isremoved but prevents any leakage of the fluid.

A biohazard containment or enclosure 70 enables spiking and withdrawalof the gene therapy drug from drug container 52 outside of the pharmacyand, indeed, outside of a hood. One end of fluid path element 24 cpenetrates and is sealed to biohazard enclosure 70. The spike, needle,or other mechanism for making fluid connection to drug container 52 isinside biohazard enclosure 70 and is sheathed to protect the operatorand enclosure 72. During use, biohazard enclosure 70 is opened, and drugcontainer 52 is placed inside. Then, biohazard enclosure 70 is sealedand container 52 is connected to fluid path 24 c using gloves or otherflexible handling devices that operate through the walls of biohazardenclosure 70. If biohazard enclosure 70 is flexible, it does not need tobe vented. If it is rigid or semi-rigid, it preferably incorporates avent, which is preferably adapted or designed to contain any aerosolizedbiohazardous material. The vent can incorporate activated charcoal or azeolite material if it is necessary or desired to contain drug vapors aswell. The in-suite biohazard enclosure 70 of the present invention savesconsiderable time, labor and expense by eliminating the syringe fillingsteps in the pharmacy. Biohazard enclosure 70 can for example, include aCaptair Field Pyramid glove box available from CAPTAIR™ LABX, INC. ofNorth Andover, Mass.

Another embodiment of a biohazard enclosure 80 of the present inventionis shown in FIG. 4. Biohazard enclosure 80 includes a vessel 81 a havinga neck 81 n that is, for example, formed, adapted or designed so thatthe outside of the neck or lid of drug container 52 fits tightly intothe inside of enclosure neck 81 n. Drug container 52 is, for example,held against the bottom of enclosure 80 by a biasing member such asspring 81 c when lid 81 b is installed onto vessel 81 a. Lid 81 b can,for example, be retained by threads or by other means. Preferably, aseal is formed between lid 81 b and vessel 81 a which is sufficient toprevent egress of any biohazard material. The seal can, for example, bemolded into either or both of lid 81 b and vessel 81 a. Alternatively,the seal can be a separate elastomeric seal. In the embodiment of FIG.4, biohazard enclosure 80 includes an optional filtered vent 81 d toallow air movement to equilibrate pressure between the inside and theoutside. During use, the needle or spike connected to the distal end(farthest from patient) of tubing 24 c first pierces enclosure septum 81s. It then is pushed farther and pierces drug container septum 52 s. Anyleakage of biohazardous drug is contained within enclosure 80. If theenclosure is designed to fit one size of bottle, then spring 81 c can befunctionally included into lid 81 b by, for example, simply bulging lid81 b inward enough that it holds drug container 52 in place. Vessel 81 aand lid 81 b can, for example, be manufactured by vacuum forming or byinjection molding. Alternatively, vessel 81 a can be flexible with aseal such as found in a ZIPLOC® bag. In this case, vessel 81 a can havea rigid or elastomeric segment that mates with the neck of the drugcontainer.

It may be advantageous if the drug bottle is distributed with anintegral biohazard enclosure such as illustrated in FIG. 4. The drugbottle can, for example, either come with the biohazard enclosure inplace, or with the biohazard enclosure in the same package, to beinstalled as soon as the package is opened. A biohazard containmentmechanism can be achieved by incorporating the double septum feature (81s and 52 s) onto neck of the container.

An alternative embodiment that provides some indication of the efficacyor patency of the sealed enclosure can be formed by connecting filteredvent 81 d to a low flow rate vacuum pump, either continuous orperiodically operating, either manual or automatic. By measuring thepressure in the enclosure, any compromise of the enclosure, will beindicated by a pressure rise and an alarm or indication can be made tothe operator.

Another embodiment of a biohazard enclosure is illustrated in FIG. 5A.In the embodiment of FIG. 5A, rather than wholly enclosing drugcontainer 52, needle 92 that pierces drug container septum 52 s ispreconnected to fluid path 24 c and is part of an “on only” cap 90 thatis pushed on once and then cannot be removed from container 52 (exceptwith considerable force and/or effort). Bumps 91 a and 91 b can, forexample, elastically deform as cap 90 is pushed on. Bumps 91 a and 91 bengage lip 52 b of the container 52 and prevent the removal of cap 90.Flexible sealing member 93 flexes to allow lip 52 b to pass, and thenseals against the neck 52 n of the container 52. The air inside cap 90is vented through vent 94. The sealing member 93 can be permanentlyattached to the cap 90, or be press fit, or be installed into the capbefore use by the user. FIG. 5B shows the sealing member 53 mounted onthe fluid container. It could come mounted or come demounted and bemounted by the user before mating with the cap 90. FIG. 5C shows a thirdembodiment, wherein the seal is between a deformable member 97 and thefront of the container neck or optionally with the front of lip 52 b. Inthis embodiment, the seal is made to deformable member 97 before theneedle 92 pierces the septum 52 s. Additional motion of the cap 90towards the container 52 maintains the seal, pierces the septum 52 s andestablishes the fluid path. The deformable member 97 or seals 93 or 53can be for example, a bellows, a thin deformable structure, asufficiently soft elastomer, a gel, a closed cell foam, or an open cellfoam with pores or surface finish sufficient to prevent egress of anyhazardous materials. If an open cell foam is used, it can incorporatethe air venting function such that a separate vent 94 is not needed. Thesealing options discussed subsequently in relation to biohazardcontainment connectors can also apply here. Alternatively, container 52and cap 90 can be provided with cooperating threading for forming asealed connection therebetween. By connecting fluid path 24 c to theother fluid path elements before connection to drug container 52, thebiohazard containment of the drug or pharmaceutical is completed withoutfull physical enclosure of container 52. While FIGS. 5A, 5B, and 5C areillustrated with a needle piercing a septum, it could also use aneedleless connector such as the InterLink® system, a make only luerconnection, or any other suitable fluid connection.

By eliminating or preventing the opening of the liquid connection, asignificant source of aerosol generation is removed by the system ofFIG. 5.

An alternative to a tightly sealed enclosure is a less tightly sealed,passive enclosure that includes germicidal, viruscidal, or chemicaldestroying agents, devices or substances. Examples of germicidal,viruscidal, or chemical destroying agents, devices or substancesinclude, but are not limited to, ultraviolet light, hydrogen peroxidevapor, activated charcoal, and ozone gas. In some circumstances,surfaces such as those coated or impregnated with silver, platinum,enzymes, activated charcoal, or Triclosan can be used.

As shown in FIG. 2, a thermal device 71 can be in thermal connectionwith the container 52. Thermal device 71 can, for example, be athermoelectric heater/cooler that can maintain the drug in a frozenstate and then controllably heat the drug to either room temperature,body temperature, or another temperature at a controlled rate. Thermaldevice 71 is connected to control unit 69 a, which coordinates itsoperation. Thermal device 71 can, for example, help maintain the drug ata reduced temperature through passive insulation or through activechilling (for example, with dry ice or with a mechanical refrigerator).Heat can be provided in many ways including, but not limited to, aresistive heater, microwaves, chemical reaction(s), material phasechange(s), or hot air.

Pump 42 can provide steady consistent flow over extended periods of time(for example, over minutes) much better than a human pushing a syringeplunger. The consistent flow provided by pump 42 reduces the riskassociated with operator fatigue and/or mistakes. Also, by making theconnection in a protected way, and then throwing away, as a unit, fluidpath 24, containers 51 and 52, enclosure 70, and other fluid pathelements, there is no opening of the fluid path that could allow thebiohazardous material to escape into the environment.

Saline, other flushing fluid or another non-hazardous drug can be storedin container 51. Flow is driven or caused by pump 41. The flushing fluidflows through tubing 24 b and 24 a, into manifold 30 and thence intopatient 1. In certain gene therapy procedures, the initial flush flowrate is preferably the same as the drug flow rate and preferably beginsimmediately after the flow of the drug is stopped, because it is used toflush drug out of the fluid path into patient 1. The saline can also bepumped simultaneously with the drug to provide dilution of the drug ifthat is advantageous. Rapid alternations between saline and drugdelivery can also produce a dilution effect with the fluids mixing asthey traverse the remainder of the fluid path. Additionally, insituations where two or more of the possible multiple fluids areincompatible, the flushing fluid can be used to separate theincompatible fluids before delivery to the patient. For example, someX-ray contrasts are incompatible with some gene therapy drugs.

Pumps 41 and 42 can be one of many commercially available pumps. Forexample, a suitable pump is the CONTINUUM™ pump available from Medrad,Inc. of Indianola, Pa. The PEGASUS™ series of pumps available fromInstech Laboratories, Inc. of Plymouth Meeting, Pa., can also be used insome applications. Depending upon the details of the procedure and thenumber of fluids to be used, multiple hazardous fluid pumps withcontainment chambers and or multiple non-hazardous fluid pumps can beused.

Where fluid lines 24 b and 24 c come together to start segment 24 a, itcan be useful to have one or more spring-loaded one way valves orelectrically controlled valves 24 d and 24 e, so that there is no flowor diffusion of one fluid into another fluid. A similar use of valvesis, for example, found on the disposable fluid path used with theSPECTRIS® MR injectors available from Medrad, Inc. to prevent diffusionmixing of MR contrast into the flushing fluid.

With the systems of the present invention, the operator can inject andflush the gene therapy drug much more consistently and conveniently thanby current hand operated procedures. The sequence, volumes, flow rates,and durations of various injections can be effected in the same manneras those currently effected by hand, or can be much more flexible,sophisticated, or complex than is possible with separate syringes andhand injections.

Another feature of the systems of the present invention that canincrease ease of use and safety is waste container 55 illustrated inFIG. 2, which is connected to manifold 30 via tubing 25. Waste container55 can, for example, be a sealed, initially collapsed bag, or a rigid orsemi-rigid container with a filtered vent. When fluid lines are firstconnected, they can be dry (full of air.) Because it is generally bad toinject air into a patient's blood vessels, it is necessary to prime orpurge the fluid lines, that is, to push fluid through the lines toremove the air. To eliminate the chance that any biohazardous materialis released into the environment, first contrast syringe 10 and manifold30 can be primed, either into waste container 55 or using the procedurescurrently done. Then the biohazardous drug is primed through 24 c andjust a little bit beyond into tube 24 a. Then the flush fluid is primedthrough 24 b and 24 a all the way into waste container 55. In thismanner, no biohazardous material is released during the purging process.In an alternative embodiment, the fluid path can be primed with, forexample, saline prior to connecting the fluid path to container 52. Such“prepriming” is discussed in U.S. Patent Application Publication No.2003-0004463, filed Jul. 2004, 2002, assigned to the assignee of thepresent invention, the disclosure of which is incorporated herein byreference.

Dashed lines 60, 61, 62, 63, 64, 65, 66, 67, and 68 in FIG. 2 representcommunication paths for information or control transmission or transfer.In the embodiment of FIG. 2, control unit 69 a communicates with thesystem pumps and the patient. Control unit 69 a also preferably includesa user interface 69 b through which the operator can monitor, program,or control all the associated devices. User interface 69 b allows theoperator to input settings or controls, and to assess the condition andoperation of the system. In one embodiment, user interface 69 b includesa display with a touch screen as known in the computer arts. Portions ofuser interface 69 b can optionally include a foot pedal, hand switch,voice recognition, voice output, keyboard, mouse, and/or an LCD display.Control unit 69 a can, for example, include a personal computer with akeyboard, speakers, and display that serves as user interface 69 b.Software such as LABVIEW® available from National Instruments of Austin,Tex., is, for example, capable of collecting data and creatingsophisticated control strategies based upon that data and may beincorporated into control unit 69 a.

Lines 60, 61, and 62 communicate with system pumps 40, 41, and 42,respectively. Line 63 communicates with manifold 30 so that the properfluid path is open at the proper time. Lines 65 and 66 can operatevalves 24 d and 24 e respectively, if they are controlled valves ratherthan spring loaded valves. Line 64 is shown schematically to bringheartbeat information from patient 1 to control unit 69 a. An instrument(not shown) can be provided that acquires the signal and conditions oroperates on it before outputting it to control unit 69 a. The instrumentcan, for example, be an ECG monitor, a blood pressure monitor, a pulseoximeter, image segment or region of interest extractor, or otherdevice. If control unit 69 a incorporates, for example, a dataacquisition card (available, for example, from National Instruments)with sufficient isolation, no additional instrument is necessary. Insituations where the target is an organ other than the heart, theinstrument can monitor some physiological parameter or imaging aspectrelated to that target organ. An example is monitoring respiration wherethe parameters of interest are respiration rate, tidal volume and endtidal volume. Other examples are peristaltic contraction of theintestines or voluntary or stimulated contraction of muscles.

There are many varieties of communication paths. For example,communication paths can be hard-wired using the presence or absence of avoltage to activate a relay, or using a standard such as RS-232. Thecontrol lines can be electrical, hydraulic, pneumatic, mechanical, orany other advantageous communications lines. Alternatively, thecommunication paths can be wireless using any one of many standardprotocols. The communication paths can also utilize IR data transmissionmethods. Additionally, one type of transmission method/protocol can beused for one communication path and another type used for a differentcommunication path.

In addition to the benefits of fluid delivery synchronization,centralized control, and common user interface, the systems of thepresent invention provide the ability to overcome the need for deepsubselective catheter placement to avoid reflux.

In that regard, during diastole, the heart muscle is relaxing and thechambers are filling with blood. At the same time, pressurized blood isstored in the aorta and is flowing into the coronary blood vessels.During systole, the heart muscle contracts, expelling blood from theinside of the heart. During this cycle the blood in the coronaryarteries undergoes a reversal in flow direction. This is termed reflux.It is not normally a problem, and is not a problem during regularangiography. Some of the contrast is simply carried back into the aortaand out into the systemic circulation.

However, for gene therapy drugs or other toxic, hazardous or strongtreatments, it is desirable to have no reflux of the hazardous substanceinto the systemic circulation or nearby vessels. In the current genetherapy practice, reflux is avoided by placing the catheter deep intothe coronary vessels. An alternative to deep placement is to synchronizethe injection of the drug with the heart beat of the patient, so thatthe drug flow is stopped sufficiently in advance such that the reflux ofblood does not bring any drug into the aorta and thence into thesystemic circulation.

FIG. 3 illustrates an example blood flow pattern and a drug injectionpattern of the present invention to prevent reflux. The drug injectionstarts after the coronary artery flow is sufficient to carry theinjection downstream and ends before the volume of blood still to passthe catheter tip is smaller than the volume of blood that is refluxed.This timing can be set with enough margin so that it operates for allpatients. Alternatively, it is possible to use an imaging system withcontrast test injections of various injection flow rates and/or timing(X-ray, MR, or ultrasound) and measure the amount and timing of refluxas related to a particular patient's ECG or blood pressure waveform. Inaddition, the catheter tip could incorporate a flow sensor that coulddirectly measure blood flow and thus provide that information to controlunit 69 a for synchronization or for calibration and confirmation oftiming in relation to the ECG and blood pressure waveform. Control unit69 a makes it relatively easy to inject contrast synchronized with theheart function, and by using the imaging to monitor for the presence orabsence of reflux of contrast, the timing of the injection terminationwith respect to the heart function can be optimized.

If pump 42 cannot start and stop fast enough to deliver the necessaryflow pulses, passive valve 24 e may be replaced by an active valve thatrapidly turns on and off to deliver sharp pulses. If there is too muchcapacitance or compliance in the fluid path from 24 e to patient 1, thenthe active valve can be moved down stream to improve the bolussharpness. The active valve can of be any suitable type including, forexample electromagnetic, piezoelectric, pneumatic, or hydraulic.

In certain situations, it may be an advantage to have pump 42 or theactive valve actually draw back a few microliters of fluid when the flowstops. This action draws a little blood into the catheter and therebyensures that as blood refluxes back from the artery into the aorta, nodrug can diffuse from the catheter and get into the aorta.

While the above has been described with respect to liquids in the bloodvessels, and in particular the coronary arteries, similar benefits ofefficient drug delivery and minimization of undesired drug migration canbe achieved by synchronizing aerosol drug delivery via the lungs. Thedrug is provided into the air stream as air is inhaled. Drug delivery isstopped before inhalation ceases, so that all of the drug is carrieddeep into the lungs. Thus there is much less or no exhalation of drug.

An alternative to reflux prevention through injection synchronization isto employ occluding balloons to stop flow for a period of time while thedrug is infused. The balloon inflation can be done manually orautomatically. The balloon inflation device is preferably incommunication with the control unit 69 a. It can be inflated for a shortperiod of time during which drug is delivered, then deflated, forexample to allow blood to nourish the heart muscle or for another breathto be taken. This procedure can be repeated a number of times. A benefitof the occlusive approach of the present invention is that the drug isnot continually being washed out of the muscle and into the venoussystem.

A two balloon occlusive system could be employed, with the drug injectedinto the space between the two balloons. This procedure allows treatmentof a selected section of a blood vessel and can, for example, be usefulto pretreat or post treat arterial segments that are being stented.

The fluid path of the system shown in FIG. 2 can come totallypreassembled, such that the only connections needing to be made theconnection to the catheter 31 and the container 52. Or, it may come asmany separate pieces that are assembled by the user. If the connectionsare made before the hazardous pharmaceutical enters the system and arenot to be subsequently opened, the connections can be simple luer lockstandard connectors. For those connections that are made or possiblebroken and remade, such as the catheter connection, after hazardousfluid has entered the system, additional precautions should be taken. Asuitable biocontainment connector will be described elsewhere.

Table 1 sets froth a brief description of the system set-up and drugdelivery steps for the current practice and for the present inventionand illustrates the improvements evident in a comparison of the requiredsteps.

TABLE 1 1. Store frozen vials in the pharmacy. a. Store frozen vials inthe pharmacy 2. In a pharmacy hood, using gloves and proper b. Transportthe drug bottle to the suite, install in technique, thaw the bottle withthe gene therapy the biohazard enclosure and thaw. (Or, install in drugin the hand, avoiding agitation. biohazard enclosure in pharmacy andtransport therein.) 3. Using a needle, pull a few ml of drug into a 10ml syringe. 4. Add a few ml of saline to dilute it. 5. Place the 10 mlsyringe in a 20 ml syringe holder for transport to the interventionalsuite to preserve the sterility of the outside of the syringe. (Thaweddrug has to be used in several hours.) 6. Operating personnel put on andwear goggles and masks with M-95 filters to protect against infectionfrom airborne virus. 7. All the fluid lines are purged of air. The c.Purge air from all fluid lines, ensuring that any operators can dilutethe drug further if there are biohazard material is delivered into thewaste more than 4 coronary arteries to inject. container 55. Connect thepatient ECG to the control unit 69a. 8. The catheter is positioned inthe desired vessel d. The catheter is positioned in the desired vesselusing normal angiographic equipment and using normal angiographicequipment (manifolds, technique. Deep subselective placement can becatheters, guidewires) and technique. used avoid any reflux of contrastor drug into Deep subselective placement is not needed. the aorta. 9.The placement is verified with a contrast e. The placement is verifiedwith a contrast injection. injection. 10. The manifold and/or catheterare optionally f. The operator programs the pumps to deliver the flushedwith saline by removing the contrast proper amount with the propertiming. syringe and attaching the saline syringe. 11. The saline syringeis disconnected, the gene therapy syringe is connected and 1 to 5milliliters is injected by hand over 1 to 2 minutes. 12. The genetherapy syringe is disconnected and the saline syringe is connected toinject a few ml of saline over the same time period to flush the genetherapy drug out of the fluid path and into the patient. 13. The salinesyringe is disconnected and the g. The drug and flush fluids aredelivered as contrast syringe is reconnected to inject programmed.contrast to confirm that the catheter had not moved. 14. The catheter isthen repositioned for the next h. The catheter is then repositioned forthe next injections and steps 8-12 are repeated until all injections andsteps d-g are repeated until all vessels are injected vessels areinjected 15. The disposable parts of the system are disposed i. Thedisposable parts of the system are disposed of as biohazard material. ofas biohazard material.

Communications and control in the systems of the present invention canhave various levels of sophistication based upon design, verification,economic, and usability considerations. A simple level involvescentralized start/stop timing or synchronization between two or moredevices. A next level can, for example, be centralized programming ofone or more pumps to improve operator or user convenience. A next levelcan, for example, involve a common programming interface for all pumps.A next level can, for example, include standard protocols involvingvarious synchronization strategies and allowing the operator to save andrecall customized protocols. The systems of the present inventionprovide great flexibility for designers to meet user needs.

Communications and control functions are shown schematically ascoordinated by control unit 69 a. However control can readily bedistributed in another fashion. For example, angiographic injectors canmonitor the ECG and synchronize the injection of contrast with theheart. The injector can then transmit the ECG signal or simplestart-stop commands to drug pump 42 so that it can synchronize druginjection with the heart. Thus, some or all of the functions of thecontrol unit 69 a can be performed by the system pumps themselves in adistributed fashion at the convenience of the product designers orusers. There need not be a specific box or piece of hardware thatperforms all, many or even any of the functions attributed to thecontrol unit 69 a. Control can be distributed.

It certain situations, it can be advantageous to have contrast injectoror pump 40, similar to that described in U.S. patent application Ser.No. 09/982,518, filed on Oct. 18, 2001, assigned to the assignee of thepresent invention, the disclosure of which is incorporated herein byreference, be the primary controller, performing many of the functionsof control unit 69 a. In this embodiment, pumps 41 and 42 communicate tocontrast pump 40 and all the operations described herein are achievable.The additional fluid delivery systems could be considered as accessoriesfor the contrast pump 40.

To check for proper fluid line purging, air detectors such as thoseavailable from Introtech of Edgewood, N.Y., can be included at variousplaces along the fluid path.

While the embodiments of the present invention described above includepumps that can be applied for the delivery of all the fluids related toa procedure, for either cost or historic preference, perception, orfeelings of wanting to be in control, some of the pumping functions canbe performed manually while others are performed mechanically.Specifically, many doctors prefer the manual “feel and control” ofconducting the contrast injection. In this case only pumps 41 and 42 areused. Alternatively, mechanical delivery can be used and tactilefeedback provided to the doctor to simulate the “feel and control” ofmanual operation. Tactile feedback is discussed in U.S. Pat. No.5,840,026 and in U.S. patent application Ser. Nos. 09/982,518 and10/237,139, assigned to the assignee of the present invention, thedisclosure of which are incorporated herein by reference.

It is also possible to select the properties of a fluid path element,for example tubing 24 a such that its volume is sufficient to hold thefull volume of the drug to be delivered. In this case, the full volumeof drug to be delivered in the single injection is relatively quicklyinjected into 24 a, and then the flushing fluid is slowly infused viapump 41, pushing the drug into the patient at the desired controlledrate. Even if the volume of tubing 24 a is not sufficient to hold thefull volume of the drug, if the system knows the volume of fluid in thevarious tubings and pumps, it can operate pump 42 at an initially highrate until the drug is just about to exit the catheter, and then slow tothe desired infusion rate. This saves time, and time is money.

Thus it is evident that any one, several, all, or none of the fluids canbe advantageously injected by pump and the remaining can be injected byhand if the user so desires.

If there is a reason for the doctor or operator to prefer a handinjection of the drug, then the device of FIG. 6 can be advantageous.The device of FIG. 6 incorporates the biohazard enclosure 80 or any ofthe various biohazard enclosures discussed herein with a multi-portvalve 100 that allows manual syringe 10 to be connected to drugcontainer 52, which is safely installed in the biohazard enclosure 80,to a source of flush fluid, saline or diluent 21, and to outlet 101,which is in fluid connection with patient 1. Outlet 101 can be aflexible tubing to connect to a catheter, or a needle for subcutaneousor intramuscular delivery of the drug. Valve 100 can, for example,include a spiked connector 100 a which penetrates septum 81 s ofenclosure 80 and septum 52 s of container 52 to place valve 100 in fluidconnection with container 52. Alternatively, valve 100 can include aflexible fluid line to biohazard enclosure 80 so that biohazardenclosure 80 can be remote from the syringe 10 and valve 100. Choosingthe fluid path connection by rotating the valve control lever, theoperator has full manual control of the filling and delivery with theaugmented safety afforded by biohazard enclosure 80 of the presentinvention.

FIGS. 7A through 7C illustrate another embodiment of a portion of afluid delivery system of the present invention. Specifically thisembodiment accomplishes steps 3 through 5 of table 1 without the needfor a biosafety hood in a pharmacy. Loading device 200 can, for example,come preassembled with a syringe 350 inside it and can be fully sterile.A vial of saline 210 and a vial of drug 212 are inserted into openingsinto in the top of loading device 200. Seals 208 seal to the outside ofthe vials and form a biohazard enclosure. The space in vented through afilter or vent (not shown). When vials 210 and 212 are fully installed,their septums have been punctured by needles (not shown). Inside chambershroud 222 is a syringe 350. The plunger in syringe 350 can be moved upand down by moving lever 230 for course motion or by turning thumbwheel240 for fine motion. Lever 250 can be switched to connect the syringefirst to saline vial 210 and then to drug vial 212. Syringe 350 can, forexample, be in fluid connection with vial 210 and vial 212 via a spike254, which is in sealed fluid connection with a self-sealing elastomericplug or septum 360 (see FIG. 7C).

To fill syringe 350 with a mixture of drug and saline, the user pushesthe two vials completely into device 200. Then with the lever 250connected to saline, the user pulls in sufficient saline to purge allair from the lines into the syringe. Then the user pushes the air andsome of the saline back into the saline container until the desiredamount of saline remains in the syringe. The user observes the syringethrough the clear shroud 222. Now the user switches lever 250, whichcan, for example, be in operative connection with a valve 252 (see FIG.7C) within the housing of device 200, to the drug position and pullsfluid from drug vial 212 into syringe 350. There will be a small,consistent volume of air pulled in with the drug. The air bubble can beminimized by minimizing tubing diameter, or it can be a known consistentvolume and thus be compensated for by the user. When syringe 350 isfilled with the desired amount of saline and drug, the syringe can beejected from device 200 by rotating shroud 222 and removing syringe 350.Syringe 350 can, for example, be ejected from device 200 withself-sealing elastomeric plug 360 on the end so that no drug can leakinto the environment. The outside or exterior of syringe 350 can bemaintained sterile so that it can be handled by sterile doctors orequipment operators. Syringe 350 could be used for hand injections, orcan be connected to a pump via, for example, a system similar to thatillustrated in FIG. 13 that preferably provided a containment to captureany aerosols or spills created during the making of a connection.

FIGS. 8A through 8C illustrate another embodiment of a portion of afluid delivery system of the present invention including anelectromechanically powered injector or pump 400 which is powered byconnection to a source of electrical energy via a power line 410 (seeFIG. 8B). In the embodiment of FIGS. 10A through 10C a multi-chamber,multi-reservoir or multi-compartment container 500 is removablyattachable to pump 400. Multi-chamber container 500 includes chambersfor containment of, for example, three different fluids which can bepumped by pump 400 when multi-chamber container 500 is operablyconnected to pump 400 as illustrated in FIGS. 8B and 8C. A first chamber510 can, for example, be in fluid connection with a source of saline(not shown) via tubing 512. A second chamber 520 can, for example, be influid connection with a source of contrast (not shown) via tubing 522. Athird chamber or enclosure 530 preferably forms a hazardous materialcontainment enclosure for use in connection with a hazardouspharmaceutical container 536 including, for example, as a gene therapydrug. Hazardous enclosure 530 can, for example, operate in a mannersimilar to enclosure 80 of FIG. 4 or similar to that shown in FIG. 5.Hazardous enclosure 530 can include a heating/cooling element orelements as discussed above.

Upon operation of pump 400, one or more of the fluids from chambers 510,520 and 530 is transmitted to the patient via tubing 560 with is influid connection with a catheter (not shown). A second tubing line 570can be provided to connect to a waste container 515 (similar inoperation to waste container 55 of FIG. 2). Second tubing line 570 canalso be used for purging air each time a connection to a catheter isbroken as, for example, when switching between blood vessels forinjection.

Pump 400 further includes a release latch 420 to enable disconnection ofmulti-chamber container 500 from pump 400. Pump 400 can further includecontrols 430 positioned upon the housing of pump 400 to control theoperation thereof. Additionally or alternatively, a control unit remotefrom pump 400 can be provided. Although containers or reservoirs 510 and520 and enclosure 530 are formed integrally in the embodiment of FIGS.8A through 8C, one skilled in the art understands that the containersand enclosure(s) can also be separately attachable to pump 400 or asimilar pump.

The system of FIGS. 8A through 8C can be used in a sterile field byencasing the reusable pump 400 in a disposable container, for example, aplastic bag, and fully contains a hazardous pharmaceutical such as agene therapy drug. Multi-chamber container 500 can be made to bedisposable. Pharmacy preparation procedures are eliminated as a resultof hazardous enclosure 530. Electromechanical pump 400 provides foruniform delivery of fluid over extended periods of time with the abilityto program complex flow control parameters.

FIG. 9 illustrates another embodiment of the present invention in whichuniform delivery of fluids over an extended period of time is automated.In this embodiment, a single disposable device 600 contains two side byside syringes, for example, a saline syringe 620 and a drug syringe 610.These can be prepared in many places, for example, in a hood in thehospital pharmacy, in the device of FIG. 7, or they preferably comepreloaded with the liquids. To fill syringes 610 and 620, the operatorpulls back handles 640 and 630 which also winds or bias springs 632 and642 that store energy for pressurization of saline and drug,respectively. A control button 650 can be provided to start the flow ofthe drug. Adjustable stop controls 660 and 670 can be provided tocontrol the amount of drug and saline, respectively, injected through anoutlet 680 into the patient. After the selected amount of drug isdelivered, the pump automatically delivers the selected amount ofsaline. Pump 600 can be disposable in its entirety.

FIGS. 10A through 10C illustrate a pump mechanism 700 that operates in asimilar manner to pump mechanism 600. Pump 700, however, useselectromechanical power to inject fluid from disposable, front-loadingsyringes 800 a and 800 b. Pump 700 can, for example, operate in a mannersimilar to the dual syringe STELLANT® and SOLARIS® injector availablefrom Medrad, Inc. Power is supplied to pump or injector 700 via powerline 710.

Syringe 800 b can include a hazardous pharmaceutical. Syringe 800 a can,for example, be in fluid connection with a fluid path 810, which is influid connection with a source of another fluid (for example, saline).Preferably Syringe 800 b with the hazardous drug comes with fluidconnections already made, or has a fluid connection such as those shownin FIGS. 13A through C such that biohazard containment is achieved.

As used herein in connection with several of the various embodiments ofthe present invention, the term “pump” includes all means of causing acontrolled fluid flow, including controlled pumps or pressure sourcesand regulators, for example peristaltic pumps, gear pumps, syringepumps, electrokinetic pumps, gravity, compressed gas, controlled gasevolving devices, spring pumps, centripetal pumps or any system whichdoes not require continuing human exertion of motive force when thefluid is flowing. A number of the aspects of the present invention canalso be advantageously applied to hand activated pumps as well.

Especially in cardiac studies, it is anticipated that more than one drugwill beneficially be injected. Examples of additional drugs are cardiacstress agents, thrombolytic drugs, or drugs to decrease the chance ofrestenosis after angioplasty or stenting. As clear to one skilled in theart, injection of such additional substances can be accommodated byadding additional pumps, fluid reservoirs, and optionally communicationslines to the systems described herein.

Non-viral gene therapy approaches can also benefit from the features ofthe systems of the present invention. While not as hazardous, non-viralgenes still may pose hazards to healthcare workers. Minis Corp. ofMadison, Wis., has, for example, published animal results in which theyinject DNA not contained in a virus into the limb arteries using higherflow rates and volumes than discussed above in connection with DNAtransfected via a viral vector. At high flow rates and volumes (over 100ml), a fluid delivery system using mechanical pumps is especiallybeneficial.

There are also studies that discuss the injection of drugs or enzymesbefore injection of a gene therapy drug or other therapeutic agent.These pretreatment drugs can, for example, promote the migration ortransfer of DNA from the blood vessel into the tissue. An example ofsuch a pretreatment drug is an enzyme that breaks down collagen to makethe blood vessels more porous to the gene's DNA. The systems of thepresent invention can be used to inject such pretreatment drugs.

The fluid delivery system of the present invention can also be used todeliver gene therapy drugs for direct injection into the heart or othertissue. In The Scientist, 14101:4 May 11, 1998, for example, a treatmentis disclosed involving the direct injection of a gene therapy drug intoheart muscle during open-heart surgery using 14 separate insulin (lowvolume) syringes and needles. The systems of the invention can eliminatethe labor, cost, and risk of filling all those syringes by allowing theoperator to inject multiple times directly from a common reservoir.Instead of delivering fluid to catheter 31 in such a procedure, it canbe delivered via a tube to a small needle that is inserted appropriatelyinto the heart muscle (myocardium). This also provides the safetyenhancement of always flushing the line with saline after the drug, sothat when a connection is opened, it is saline flush that has thepotential for spillage or aerosolization, rather than the hazardousdrug. In a situation such as this, it is beneficial if the userinterface tells the user when the injection has been completed, and thehazardous drug has been flushed from the line so that the connection canbe opened or the needle removed.

The fluid delivery system of this invention can also be used to deliverthe fluid in connection with other gene uptake augmentation schemes, forexample sonoporation, electroporation, or optically activated drugdelivery strategies.

The fluid delivery systems, devices and methods of the present inventionhave been generally described above using representative examples ofinjection of gene therapy drugs or agents. However, the systems, devicesand methods of the present invention are not limited to gene therapyapplications. The systems, devices and methods of the present inventioncan be used in many other drug delivery and therapeutic procedures. Ingeneral, the systems, devices and methods of the present invention areparticularly suited for use in connection with any hazardouspharmaceutical or substance to be injected into a patient (human oranimal). As used herein, the term “pharmaceutical” refers to anysubstance or drug to be injected or otherwise delivered into the body(either human or animal) in a medical procedure and includes, but is notlimited to, substances used in imaging procedures (for example, contrastmedia), diagnostic, and therapeutic substances. As described above inconnection with gene therapy agents, a number of such pharmaceuticalsubstances pose a danger to both the patient and to the personneladministering the substance if not handled and/or injected properly.Examples of hazardous pharmaceuticals include, but are not limited to,radiopharmaceuticals, biological pharmaceuticals, proteins, cells (forexample stem cells or myogenic cells), chemotherapeutic pharmaceuticalsand gene therapeutic pharmaceuticals. Examplary methods of administeringhazardous pharmaceuticals include intraarterial, intravenously,intramuscularly, subcutaneously, by respiration into the lungs, andtransdermally. Even pharmaceuticals that are not considered to beextremely hazardous can be beneficially administered via this system andprovide hospital personnel additional protection against adverseeffects.

The systems of the present invention can, for example, be applied toradiotherapy drugs or pharmaceuticals wherein the drug or pharmaceuticalitself is radioactive. As clear to one skilled in the art, maintainingcomplete containment of radiotherapy pharmaceuticals promotes safety. Ifthe drug or pharmaceutical is radioactive, the use of radiationabsorbing or leaded Plexiglas shielding will help protect the operatorand patient from unnecessary radiation dose. Designers skilled in theart of radiation shielding can readily specify the thicknesses needed.Containment of radiotherapy pharmaceutical is discussed in U.S. PatentApplication Publication No. 2003-0004463.

When used in connection with thrombolytic pharmaceuticals, the systemsof the present invention provide, for example, the benefit of integratedcontrol and the ability to inject the thrombolytic pharmaceutical, toinject saline, and to periodically inject contrast to verify continuedcorrect placement of the catheter.

Likewise, the systems of the present invention can be advantageouslyapplied to tumor and other chemotherapy in which the chemotherapypharmaceutical is supplied to the vessels supplying a tumor or otherregion of interest. In the case of chemotherapy pharmaceuticals, thefluid volumes can be quite small and an occlusion balloon can bebeneficial to slow or prevent the wash out of the chemotherapy from, forexample, tumor tissue.

The pharmaceuticals or drugs mentioned above, or other pharmaceuticalsor drugs can be included in or associated with ultrasound bubbles. Thesystem of the present invention can deliver the bubbles to the region ofinterest and then ultrasound energy can be used to destroy the bubblesand promote the delivery of the drug to the tissue. The uses ofultrasound bubbles to deliver and release a pharmaceutical to a regionof interest is disclosed in U.S. Pat. No. 6,397,098, assigned to theassignee of the present invention, the disclosure of which isincorporated herein by reference.

The procedure of this invention has generally been described with liquiddrugs, and can also apply to powdered drugs with either a liquid orgaseous vehicle, or gaseous drugs that are to be delivered to arecipient.

A number of the hazardous pharmaceuticals for use in connection with thesystems, devices and methods of the present invention can causesignificant damage to the vessels into which they are injected. Certainantitumor chemotherapy pharmaceuticals, for example, are known to causevessel damage when delivered through a peripheral venous catheter. FIGS.11A through 11C illustrate an embodiment of an end portion of a dual,generally concentric lumen catheter 900 of the present invention thatcan be used to reduce vessel damage. In that regard, a first, outer tubeor conduit 910 is provided. A second, inner tube or conduit 920 isprovided within first tube 910 held by members 915 so that an outerlumen for passage of fluid and an inner lumen for passage of fluid arecreated. A fluid that does not cause vessel damage such as saline 950 ispreferably passed through the outer lumen. Hazardous pharmaceutical 960is preferably passed through the inner lumen.

FIG. 11C illustrates the fluid in the catheter 900. For an injection,saline starts flowing through lumen 911. No drug flows through lumen921. After a predetermined time, drug flows through 921 and saline flowoptionally is reduced by the same flow rate, so that the flow rate offluid exiting the catheter remains constant. These flow transitions arepreferably not instantaneous. When sufficient drug has been injected,then the flow of drug is reduced to 0 and the flow of saline isincreased to compensate for it. After a small amount of time, the flowof drug is reversed to pull a little saline into lumen 921, as show inFIG. 11C. Then the flow of saline is stopped or reduced. In this onecycle, the full dose of pharmaceutical 960 can be delivered, or the dosecan be delivered over a number of these cycles. This specific flowprofile is given as a example of many flow profiles that can change overtime.

FIG. 11D illustrates the resultant flow profile within a vessel 1000. Asillustrated in FIG. 11D, vessel 1000 is protected from contact withhazardous pharmaceutical 960 in the vicinity of the catheter tip by anencompassing boundary of saline. As the fluid travels down the path ofvessel 1000, diluted hazardous pharmaceutical 960 may contact vessel1000 some point, although by selecting the viscosity of the drug 960 itis possible that the bolus travels relatively undisturbed to, forexample, the heart.

This flow sequence of saline and drug delivery can be continuous, untilall the drug is delivered, or if desired, it can be repeated over timeto spread out the drug delivery and give the patient's system anopportunity to accommodate itself to the drug, minimizing the sideeffects. This periodic pulsed delivery has several other advantages. Forexample, it is easier for an extravasation detection system to operate.Extravasation detector 1100 (represented schematically in FIG. 11D)needs only to monitor for extravasation during the brief injection timeand thus is less susceptible to base line drifts that plague continuousinfusion extravasation detection schemes. Extravasation detectorssuitable for use in connection with the present invention are disclosed,for example, in U.S. Patent Application Publication Nos. 2003-0036674and 2003-0036713, assigned to the assignee of the present invention, thedisclosures of which are incorporated herein by reference. Anotherbenefit is that the initial several milliliters can be saline, so thatif an extravasation is detected, and the injection is stopped, nohazardous drug has been injected into the patient's tissues.

The systems, devices and methods of the present invention have beendescribed generally in connection with treatment of a human. However,the systems, devices and methods of the present invention can also beused to treat any animal or living system in which it is desirable toprovide the benefits of convenience, consistency, and safety to theapplication of hazardous (for example, biohazardous or chemicallyhazardous) pharmaceuticals.

An additional embodiment of the present invention is shown in FIG. 12.Module 1200 of FIG. 12 is, for example, disposable and manuallyoperated. The components are a part of or connected to a base plate 1230that incorporates fluid channels, such as 1224 c. The hazardous drugcontainer 1265 is inserted into biohazard enclosure 1270 creating a sealsuch that any aerosols created are contained within the enclosure.Container 1265 can, for example, be punctured or otherwise opened sothat fluid can flow into fluid conduit 1224 c. By pulling back on theplunger of syringe 1212, the drug is pulled through fluid conduit 1224 cand valve 1242 into syringe 1212. A saline container 1295 is connectedthrough tubing 1290. Syringe 1211 is filled with saline. Because thewhole assembly is preferably small, sterile, and light, it can be easilytilted up and down for bubble removal. To fill the remaining fluid lineswith liquid, valves 1242 and 1243 are turned so that syringe 1212communicates with waste container 1255. Air can then be ejected fromsyringe 1212 and the intervening fluid path into waste container 1255.To avoid wasting the hazardous drug, syringe 1212 can be moved forwardjust enough to move the meniscus of the hazardous drug just past valve1243 toward waste container 1255. Then valve 1241 and valve 1243 areturned so that saline syringe 1211 communicates with waste container1255. The assembly is tilted so that any air in syringe 1211 moves outand into waste container 1255 as syringe 1211 is pushed forward. Thiswill fill the remainder of the fluid path to the waste container withliquid. Then valve 1243 is turned so that syringe 1211 communicates withoutlet 1280. Syringe 1211 is moved forward and saline is pushed toconnector 1280 to remove all the air before connection to the patient.

By turning valve 1243 and operating syringes 1212 and 1211, hazardousdrug and saline can be injected in sequence, as directed by theoperator. While this embodiment does not have all the automatic featuresand safeguards of some of the other embodiments, it has the benefits ofbeing totally disposable and having an initial lower cost than some ofthe devices that have reusable system components. Because syringe 1212can be refilled in a safe manner from the drug container in theenclosure 1270, syringe 1212 can have a smaller volume and thus have asmaller diameter, which makes hand injections more accurate.

Alternatively, the module 1200 can be adapted to fit onto a reusablemotive device 1300, which could for example move the two syringe pistonsand turn the valves so that operation is automated. For example, themodule 1200 could be attached to the front of a device similar inoperation to device 700 illustrated in FIG. 10A. The module 1200 couldbe supported through the syringes or alternatively an additionalmounting bracket (not shown) could be incorporated onto device 1300. Themounting bracket could also hold solenoids, motors, or other actuatorsto automatically activate valves 1241, 1242, and or 1243. Thus theoperation can be fully automatic and have the built-in safeguardsdescribed elsewhere herein. A significant benefit of this embodiment ofFIG. 12 is the option of making a single disposable module 1200 that canbe used by hand when, for example, a hospital cannot afford a reusablemotive device, and can be mated with a reusable motive device whenrequired or desired.

FIGS. 13A through 13D set forth several embodiments of connectors forjoining two fluid path segments that include elements to containspillage and aerosols created during making and optionally breaking offluid path connections. The embodiments of FIGS. 13A through 13D setforth connectors that provide a modification or an improvement of theconnectors set forth in U.S. Pat. No. 6,440,107 B1, assigned to theassignee of the present invention, the disclosure of which isincorporated hereing by reference.

The connectors of FIGS. 13A through 13D have a number of elements incommon and such like elements are number commonly. Aseptic connectors1450 a, 1450 b and 1450 c include a first or female member 1455 and asecond or male member 1475. First member 1455 is generally cylindricalin shape and comprises a septum 1460 enclosing one end thereof. Firstmember 1455 also includes an extending member 1462 to which a conduit orconnector (not shown) such as flexible tubing or a luer connector can beattached. Extending member 1462 has a passage 1464 formed therein whichis in fluid connection with an interior 1466 of first member 1455. Firstmember 1455 also preferably comprises threading 1470 on an exterior wallthereof.

Second member 1475 includes a penetrating member 1480. Penetratingmember 1480 comprises a generally cylindrical penetrating element 1482extending from a first end thereof. A passage 1484 is formed throughpenetrating element 1482 and the remainder of penetrating member 1480.The second end of penetrating member 1480 forms an extending member 1486in fluid connection with passage 1482 to which a conduit or connector(not shown) such as flexible tubing or a luer connection can beattached.

Second member 1480 also includes a swivel member 1490 rotatablyconnected to penetrating member 1480 as described above. Swivel member1490 further includes threading 1492 on an interior surface thereof tocooperate with threading 1470 on first member 1455. Second member 1475also includes opposing wing elements 1494 extending radially outwardtherefrom to facilitate rotation of second member 1475 relative to firstmember 1455 to form a threaded connection of first member 1455 andsecond member 1475.

The cooperation of first member 4155 and second member 1475 to form anaseptic connection is illustrated, for example, in FIG. 13D. Firstmember 155 and second member 1475 are first drawn axially together. Aspenetrating element 1482 pierces flexible septum 1460, swivel member1490 is rotated relative to first member 1455 to engage threadedportions 1470 and 1492. As threaded portions 1470 and 1492 aretightened, bringing first member 1450 and second member 1475 in closercontact, a forward surface 1472 of first member 1455 contacts anannular, elastomeric member 1496 seated in a generally cylindricalinterior chamber 1498 of second member 1475. Annular, elastomeric member1496 is thereby compresses generally symmetrically around penetratingmember 1480 and against the inner wall of swivel member 1490 to create atight and substantially leakproof seal between penetrating member 1480and the interior wall of swivel member 1490. As discussed above, thesubstantial axial and radial forces upon annular, elastomeric member1496 (and the resultant seal) enable use of aseptic connector 1450 atrelatively high pressures.

As the connector of U.S. Pat. No. 6,440,107 B1 is assembled, the air andthence aerosols or spillage in the space 1500 (see FIG. 13A) is expelledfrom between the fluid path elements. The threads 1470 and 1492 providea force but are not designed to seal air within the connector. Moreover,if threads 1470 and 1492 did seal air, then air pressure would build upas the connector was assembled.

In the embodiment of FIG. 13A, circumferential elastomeric or flexiblesealing elements 1510 are attached to female connector 1455. Inaddition, elastomeric member 1496 is sized so that it seals the gapbetween penetrating member 1480 and swivel member 1490. When sealingelements 1510 contact male connector 1475, they form a seal to thatconnector's inner surface. The seal is maintained as threads 1492 aretraversed. Alternatively as shown in FIG. 13B, sealing surfaces 1520 canbe located on the inside of male connector 1475. To allow the airtrapped between the two connectors to escape, the embodiment of FIGS.13C and 13D includes a gas vent 1530. Vent 1530 preferably incorporatesa micro porous filter or plug which allows air to escape but trapsaerosols and spillage. Both hydrophilic or hydrophobic materials willprovide some containment of aerosols. For example GORETEX®, TYVEK®, andfused polyethylene plugs are commonly used for this purpose. Activatedcharcoal can be incorporated in vent 1530 so that both the vapor phaseand aerosols or spillage of various types of drugs are retained.

The sealing members could be incorporated into the threads themselves,by being elastomeric so that a tight fit is achieved or hollow so thatthey can flex sufficiently. In addition, instead of many full rotationsas shown in FIGS. 13A, 13B, and 13C, a multiple threaded with only ¼turn could be used to achieve the tightening effect and make it easierfor the sealing to be achieved.

An alternative to incorporating a vent is to arrange for the air toenter the fluid path as the connector is brought together. Anotheralternative is to have sealing elements 1510 or 1520 incorporate opencelled foam or other micro porous material such as Tyvek®, preferablyincorporating activated charcoal as well, so that the air can ventthrough or at the seal, but drug material cannot escape.

Because positioning the angiographic catheter 31 of FIG. 2 requires thata connection be opened with the potential for release of the hazardousdrug, it is advantageous if the connector of FIGS. 13 be used, with themake connector 1455 with a septum being connected on the fluid sourceside of the fluid path and connector 1475 without a septum being anintegral part of the catheter.

Although the present invention has been described in detail inconnection with the above embodiments and/or examples, it should beunderstood that such detail is illustrative and not restrictive, andthat those skilled in the art can make variations without departing fromthe invention. The scope of the invention is indicated by the followingclaims rather than by the foregoing description. All changes andvariations that come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

1. An assembly for connection to an injector comprising a retentionmechanism to retain the assembly and a pressurizing mechanism topressurize one or more fluids within the assembly for delivery to apatient, the assembly comprising: at least a first compartment definingan enclosure adapted to enclose a hazardous pharmaceutical containerenclosing a hazardous pharmaceutical, the first compartment beingadapted to prevent hazardous materials from escaping from the firstcompartment into the surrounding environment; the at least a firstcompartment including a first connector to establish a fluid connectionwith the hazardous pharmaceutical vessel; and at least a first outlet influid connection with the first connector.
 2. The assembly of claim 1further including at least a second compartment adapted to contain afluid other than the hazardous pharmaceutical, the second compartmentbeing in fluid connection with the first outlet.
 3. A containercomprising a flexible sealing member that cooperates with a connector tocreate a biohazard seal during connection of the container to theconnector.
 4. The container of claim 3 wherein the flexible sealingmember is circumferential.
 5. The container of claim 3 where in theflexible sealing member is axially compressed during connection.
 6. Aconnector comprising a first member and a second member, at least one ofthe first member or the second member comprising a biohazard sealadapted to contain biohazardous material during connection of the firstmember and the second member.
 7. A container for a biohazardousmaterial, the container including a first septum sealing a port into thecontainer and a second septum sealing the port, the second septum beingspaced from the first septum.
 8. A system for delivering a hazardousfluid to a patient comprising: a container suitable for holding ahazardous fluid and comprising a hazardous enclosure to shield againstharmful effects of the hazardous fluid; and a pump device capable ofpumping the hazardous fluid from the container and delivering thehazardous fluid to the patient; wherein the container is adapted to beremovably attachable to the pump device.
 9. The system of claim 8wherein the hazardous fluid comprises a radiopharmaceutical fluid andthe hazardous enclosure is radiation shielded.
 10. The system of claim 8wherein the container comprises a heating/cooling element forheating/cooling the hazardous fluid.
 11. The system of claim 8 whereinthe container is removably attached to the pump device via a releaselatch.
 12. The system of claim 8 wherein the pump device comprisescontrols positioned on the body of the pump device to control operationof the pump device.
 13. The system of claim 8 further comprising aremote control device associated with the pump device to controloperation of the pump device.
 14. The system of claim 8 wherein thecontainer is disposable.
 15. The system of claim 8 further comprising asecond container removably attachable to the pump device and containinga different fluid from the hazardous fluid.
 16. The system of claim 15wherein the hazardous fluid comprises a radiopharmaceutical fluid andthe different fluid comprises a diluent fluid.
 17. The system of claim15 further comprising a mixing device associated with the pump devicefor mixing the hazardous fluid and the different fluid for delivering afluid mixture of the hazardous fluid and the different fluid to thepatient.
 18. The system of claim 15 wherein the mixing device comprisesa sterile tubing set for mixing the hazardous fluid and the differentfluid.